Absence of Excretion of the Active Moiety of Bisacodyl and Sodium

Drug Metab. Pharmacokinet. 26 (5): 458464 (2011). Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) Regular Article Absence of Excretion of the Active Moiety of Bisacodyl and Sodium Picosulfate into Human Breast Milk: an Open-label, Parallel-group, Multiple-dose Study in Healthy Lactating Women

Christian FRIEDRICH1,*,ErikaRICHTER2,DirkTROMMESHAUSER3, Sandra DE KRUIF4, Thijs VAN IERSEL5,KenMANDEL6 and Ulrika GESSNER7 1Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany 2Medical Data Services, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany 3Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim GmbH & Co. KG, Ingelheim, Germany 4Medical Department, Boehringer Ingelheim BV, Alkmaar, The Netherlands 5Xendo Drug Development BV, Groningen, The Netherlands 6KGM Innovation Associates, Inc., Fairﬁeld, Ohio, USA 7Consumer Health Care Mature Markets, DMRA, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk

Summary: The aim of this study was to determine whether administration of the prodrugs bisacodyl (Bisa) and sodium picosulfate (SPS) leads to excretion of their common active metabolite, bis-(p-hydroxyphenyl)- pyridyl-2-methane (BHPM), in breast milk. Two groups of 8 healthy lactating women who had stopped breast feeding received multiple doses of Bisa or SPS. Plasma, urine, and breast milk were collected and concentrations of free and total BHPM were determined using validated liquid chromatography/mass spectrometry methods. BHPM remained below the limits of detection in breast milk following single- and multiple-dose administration of Bisa and SPS. First, BHPM plasma concentrations were observed after a lag

time of about 3 to 4 h and 4 to 5 h following Bisa and SPS administration, respectively. Cmax was attained approximately 5 h after dosing of Bisa and 9 h after dosing of SPS. BHPM did not accumulate after multiple administrations of Bisa and only slightly accumulated following multiple doses of SPS. About 12% and 13% of Bisa and SPS was excreted as BHPM into urine at steady state. BHPM, the active moiety of Bisa and SPS, was not excreted into human breast milk. Hence, use of Bisa or SPS to treat constipation of breast-feeding women is considered well tolerated with regard to exposing infants to BHPM via breast milk.

Keywords: bisacodyl; sodium picosulfate; pharmacokinetics; lactating women; breast milk; constipation; laxative

infrequent bowel movements, passing hard stool, straining, Introduction sensing that bowel movements are incomplete or unsatis- Constipation is one of the most commonly occurring factory, and having the need for manual maneuvers to disorders and has an incidence of up to 27% in otherwise facilitate bowel movements.1¥ healthy individuals.1®7¥ In a multinational survey, the Possibly due to its common occurrence, its episodic incidence of self-reported constipation ranged from 5% in symptom pattern, and generally understood symptoms, Germany to 18% in the US.8¥ Epidemiology studies have most individuals who suffer from constipation self-diagnose also reported that constipation occurs in all age groups and self-manage the condition.6®8¥ Hence, treatment consists and has generally a higher incidence among women than primarily of life-style changes ¤mainly improving diet and men.2,4,7,9®11¥ Constipation has multiple symptoms, including increasing intake of liquids¥ and use of non-prescription

Received; January 24, 2011, Accepted; May 31, 2011 J-STAGE Advance Published Date: June 21, 2011, doi:10.2133/dmpk.DMPK-11-RG-007 *To whom correspondence should be addressed: Christian FRIEDRICH, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88400 Biberach, Germany. Tel. +49-7351-54-94929, Fax. +49-7351-54-90170, E-mail: Christian.Friedrich@boehringer- ingelheim.com This study was sponsored by Boehringer Ingelheim, Germany.

458 Bisacodyl and Sodium Picosulfate Pharmacokinetics 459

Fig. 1. Metabolism of bisacodyl (left) and sodium picosulfate (right) to yield the active drug laxatives which are widely available. These agents, when bisacodyl and sodium picosulfate ¤10 mg once daily¥ and indicated for short-term use, are generally effective, and for its potential for excretion into breast milk. Bisacodyl and most individuals provide symptomatic relief within hours or sodium picosulfate are widely available as non-prescription a few days of treatment. Common non-prescription laxatives laxatives. Labeling allows dosing of 5 to 10 mg daily. Hence include bulk fiber, osmotic agents, surfactant agents, and the selection of a 10-mg dose is consistent with label usage stimulant laxatives. The latter increase propulsive motility recommendations, reflecting the highest approved dose. in the colon to promote defecation and thereby reduce ¥ Methods residence time of stool in the colon.12 Since constipation can affect people of all ages, it is also This open-label, parallel-group treatment study was common among women during pregnancy and lactation. conducted at a single site, Xendo Drug Development, BV, Hence, it is important to understand the pharmacokinetics of Groningen, The Netherlands. Sixteen healthy, postpartum laxatives in women when breast feeding and the potential for lactating women aged 23®38 years were included. Eight excretion of the drug into breast milk. women received enteric coated bisacodyl tablets ¤as Bisacodyl ¤Dulcolax¥ and sodium picosulfate ¤Laxoberal¥ Dulcolax¥ and 8 received sodium picosulfate ¤Laxoberal¥ as are commonly used stimulant laxatives. Both compounds a liquid preparation. Inclusion criteria required women aged are prodrugs, and as such have no intrinsic laxative activity 18 to 50 years who had been breast feeding their infant for themselves. However, as shown in Figure 1, both are at least 14 days, had stopped breast feeding prior to starting converted within the gut into the same active metabolite, the study, produced at least 200 mL of breast milk per day bis-¤p-hydroxyphenyl¥-pyridyl-2-methane ¤BHPM¥, which ¤verified during screening¥, had a BMI : 35 kg/m2, had a causes the desired laxative effect.13,14¥ As shown in the negative pregnancy test, and were using an acceptable figure, conversion of bisacodyl is mediated by the action of method of contraception. All subjects gave informed endogenous deacetylase enzymes found on the mucosa of the consent. Exclusion criteria included clinically relevant small intestine and colon, whereas picosulfate is converted findings observed during the screening visit or a medical by the action of desulfatase enzymes localized on colonic history that could interfere with the participation or safety microflora. Following conversion, BHPM partly reaches the of subjects. Use of other medications, with the exception of systemic circulation and undergoes enterohepatic clearance acetaminophen and hormonal therapy, was contraindicated. as its glucuronide salt;13,15,16¥ neither sodium picosulfate Smoking was limited to no more than 10 cigarettes/day. nor bisacodyl is absorbed from the gut to a significant The primary objective of the study was to determine degree.16,18,19,20¥ To ensure that bisacodyl is activated to whether multiple oral administration of bisacodyl or sodium BHPM in the colon and to limit the absorption of bisacodyl, picosulfate at a dose of 10 mg/day leads to significant the substance, if administered orally, is taken as an enteric excretion of their common active metabolite, BHPM, into coated tablet that does not disintegrate until it enters the breast milk. As a secondary objective, the pharmacokinetics colon. of BHPM in plasma, urine, and milk were investigated. The This study evaluated the single-dose and steady-state pharmacokinetic parameters of BHPM were calculated after pharmacokinetics of BHPM following multiple oral dosing of the first and after the seventh dose ¤day 8¥ of bisacodyl and

Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) 460 Christian FRIEDRICH, et al. sodium picosulfate using WinNonlin 5.2. Safety was assessed Table 1. Demographics of treated subjects by the reporting of any adverse events during the whole Bisacodyl group Picosulfate group All subjects study as well as by the vital signs and the 12-lead ECG and laboratory test results recorded at screening and on the last Number of subjects 8 8 16 ª «¤ + ¥ + + + visit day. Age years mean SD 30.6 2.5 31.8 4.3 31.2 3.5 The study design required subjects to visit the test site Height ªcm«¤mean + SD¥ 170.9 + 5.1 170.4 + 7.2 170.6 + 6.0 only for the initial screening and end-of-study visits. Weight ªkg«¤mean + SD¥ 72.4 + 6.6 71.5 + 18.9 71.9 + 13.7 Supervised daily drug administrations and the pharmaco- BMI ªkg/m2«¤mean + SD¥ 24.8 + 1.7 24.4 + 4.8 24.6 + 3.5 kinetic procedures could be conducted at the subjectsö Smoking status ¤n¥: homes. Screening to determine eligibility was conducted Never 5 2 7 between 22 and 2 days prior to initiating treatment. Two Ex-smoker 1 4 5 days before initiating treatment, subjects were instructed on Current 2 2 4 how to complete their daily diaries, use the pump to collect breast milk, and on the collection and storage of urine and milk samples. During the 24-h period prior to initiating the following, free BHPM describes unconjugated BHPM, treatment ¤day %1¥, subjects collected at least 200 mL of whereas total BHPM refers to the sum of glucuronidated and breast milk, which served as a baseline sample; subjects who nonglucuronidated BHPM. did not produce this volume were not eligible to enter the Results treatment phase of the trial. Subjects received either 10 mg of bisacodyl ¤two 5-mg Dulcolax enteric coated tablets¥ or Sixteen lactating women, mean ¤+ SD¥ age 31.2 + 3.5 10 mg of sodium picosulfate ¤20 drops of Laxoberal liquid¥ in years ¤range 23 to 38 years¥, were included; 8 subjects the morning of day 1 and days 3®8 of the study ¤no drug received bisacodyl and 8 received sodium picosulfate. All was administered on day 2¥. A standardized breakfast was subjects were Caucasian and all completed the trial. The consumed 1 h after dosing. demographics of the subjects are shown in Table 1. Body Blood samples ¤5mL¥ were obtained from a forearm vein weight ranged from 52 to 84 kg, with the exception of one 5 min prior to and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 24, subject who had a body weight of 111 kg. 28, 32, and 48 h after dosing on days 1 and 8. In addition, a Free and total BHPM in breast milk after oral single 5-mL blood sample was obtained prior to dosing in administration of 10 mg bisacodyl or 10 mg sodium the morning of days 3, 4, 5, 6, and 7. Blood was collected, picosulfate: Levels of both free and total BHPM centrifuged ¤10 min at 2000®4000 g¥ within 30 min, and excreted into breast milk remained below the limits of stored on ice. Two 1-mL aliquots of plasma were transferred detection ¤1 ng/mL¥ in all subjects after administration into cryogenic vials, stored at %70ôC at the research facility of either bisacodyl or sodium picosulfate once daily ¤10 and shipped on dry ice to the analytical laboratory. mg/day¥ on all study days. Thus no pharmacokinetic A single baseline urine sample was obtained at least 2 h parameters were calculated for breast milk. prior to dosing on day 1. Subsequently, all voided urine was Pharmacokinetics of BHPM after oral adminis- collected for the following time intervals after the ﬁrst dose tration of 10 mg bisacodyl: Free BHPM could not ¤day 1¥ and the last dose ¤day 8¥:0®4, 4®8, 8®12, 12®24, be measured in plasma; it was measured only at low and 24®48 h. Urine was collected in pre-weighed containers concentrations in the urine of a very few subjects. Therefore and stored by subjects until transfer to the research center. pharmacokinetic parameters were calculated based on Urine samples were homogenized, and two 3-mL aliquots total BHPM concentrations ¤sum of free BHPM and BHPM were transferred into cryogenic vials and stored at %70ôC glucuronides¥ only. Consequently, the parameters pres- until shipment on dry ice to the analytical laboratory. ented for total BHPM can be seen as surrogates for the All breast milk ¤minimal volume 10 mL each collection; pharmacokinetic characteristics of BHPM glucuronide. collection time recorded¥ was collected from day %1 until Single-dose and steady-state pharmacokinetic parameters day 9; samples were stored under refrigeration until transfer are summarized in Tables 2 and 3, and plasma concen- to the study center. Following homogenization, two 3.0-mL tration proﬁles ¤mean + SD¥ for total BHPM ¤free ¦ aliquots were transferred to cryogenic vials and stored at glucuronidated BHPM¥ over the 8 days of the study are %70ôC until shipment on dry ice to the analytical laboratory. shown in Figure 2. Following dosing of bisacodyl on day 1, Concentrations of free and total ¤free ¦ glucuronidated¥ total BHPM in plasma increased rapidly after a lag time of bis-¤p-hydroxyphenyl¥-pyridyl-2-methane ¤BHPM¥ in plas- about 4 h; a similar effect was observed at steady state with a ma, urine, and breast milk were determined using validated lag time of about 3 h. Cmax ranged from 20.5 to 195 ng/mL high performance liquid chromatographic methods coupled ¤geometric mean, 64.6 ng/mL¥ and 19.7 to 118 ng/mL to tandem mass spectrometry ¤HPLC-MS/MS¥ with a lower ¤geometric mean, 60.7 ng/mL¥ on day 1 and day 8 limit of detection of 1 ng/mL in all matrices at AAIPharma respectively, and was attained about 4®5 h after dosing ¤ ¥ Deutschland GmbH & Co. KG, Neu-Ulm, Germany. In median tmax . Geometric mean AUC after single dosing

Table 2. Noncompartmental pharmacokinetic parameters for total BHPM following a single oral 10-mg dose of bisacodyl or sodium picosulfate

Bisacodyl, 10 mg Sodium picosulfate, 10 mg ¤n © 8¥ ¤n © 8¥ gMean gCV ¤%¥ gMean gCV ¤%¥

AUCW ªng-h/mL« 471 54.1 209 49.7 ª « Cmax ng/mL 64.6 93.3 18.1 41.2 ª «a ® ® tmax h 5.0 3.0 24.0 9.0 6.0 10.0 ª « t1/2 h 7.7 41.1 7.3 38.6 ª « MRTpo h 13.8 44.0 15.7 19.7 ª « CL/F mL/min 272 54.1 459 49.7 Fig. 2. Mean (+ SD) plasma concentration-time proﬁle of total ª « Vz/F L 181 78.0 291 43.7 BHPM following multiple oral doses (day 1 and day 3 to 8) of ª « 10 mg bisacodyl CLR,0®24 mL/min 47.8 12.9 52.6 28.1 Results are presented as geometric means ¤gMean¥ and geometric coefﬁcients of variation ¤gCV¥. a tmax is reported as median and range. MRTpo, mean residence time after oral administration. Vz/F, apparent volume of distribution.

Table 3. Noncompartmental pharmacokinetic parameters for total BHPM after multiple 10 mg doses of bisacodyl or sodium picosulfate

Bisacodyl, 10 mg Sodium picosulfate, 10 mg ¤n © 8¥ ¤n © 8¥ gMean gCV ¤%¥ gMean gCV ¤%¥ ª & « AUCØ,ss ng h/mL 311 75.3 275 25.1 ª « Cmax,ss ng/mL 60.7 64.4 21.3 24.8 ª «a ® ® + ﬁ tmax,ss h 4.0 3.0 8.0 9.0 0.0 24.0 Fig. 3. Mean ( SD) plasma concentration-time pro le of total BHPM following multiple oral doses (day 1 and day 3 to 8) of t ªh« 8.1 63.7 10.0 37.3 1/2,ss 10 mg sodium picosulfate RAc¤AUC¥ 0.80 35.5 1.59 50.5

RAc¤Cmax¥ 0.94 65.7 1.18 44.7 ª « ¤ ¥ ¤ ¥ MRTpo,ss h 11.9 31.4 22.3 36.3 t1/2 and steady-state dosing day 8, t1/2,ss were similar. ª « ¤ ¥ CL/Fss mL/min 412 75.3 349 25.1 The apparent plasma clearance CL/F, CL/Fss was low: ª « 272 and 412 mL/min after a single dose and at steady state, Vz/Fss L 289 85.2 300 50.1 respectively. The volume of distribution was high, i.e., 181 L CL ªmL/min« 50.0 15.6 46.2 26.9 R,ss after a single dose and 289 L at steady state. Results are presented as geometric means ¤gMean¥ and geometric coefficients of variation ¤gCV¥. Pharmacokinetics of BHPM after oral adminis- a tmax,ss is reported as median and range. tration of 10 mg sodium picosulfate: Single-dose and steady-state pharmacokinetic parameters are summarized in Tables 2 and 3, and plasma concentration profiles ¤ ¥ ¤ ¥ ¤ + ¥ ¤ ¦ AUCW and at steady state AUCØ,ss were 471 and mean SD for total BHPM free glucuronidated 311 ng&h/mL, respectively. BHPM did not accumulate in BHPM¥ over the 8 days of the study are shown in Figure 3. plasma following daily administration of 10 mg bisacodyl. Just as for bisacodyl, there was a lag time of 3 to 4 h before ¤ ¥ Geometric mean accumulation ratios RAc based on Cmax observing a detectable level of plasma BHPM following and AUC were 0.94 and 0.80, respectively. oral administration of sodium picosulfate. Median tmax after In general, moderate to high inter-individual variability single and multiple administrations of sodium picosulfate was was observed for drug plasma concentrations measured at all 9.0 h, considerably longer than that observed with bisacodyl. sampling time points. Geometric mean trough concentra- Cmax for sodium picosulfate ranged from 9.2 to 29.7 ng/mL tions of total BHPM before administrations on days 4 to 8 ¤geometric mean, 18.1 ng/mL¥ and 13.0 to 27.1 ng/mL ranged from 3.0 to 3.6 ng/mL. These data suggest that ¤geometric mean, 21.3 ng/mL¥ after single and multiple the steady state for bisacodyl was achieved on the fifth day dosing, respectively. Geometric mean AUCs after single ¤ ¥ ¤ ¥ of the study at the latest. As shown in Tables 2 and 3, dosing AUCW and at steady state AUCØ,ss were 209 and geometric mean terminal half lives following single ¤day 1¥ 275 ng&h/mL, respectively. There may be slight accumu-

Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) 462 Christian FRIEDRICH, et al. lation of BHPM after multiple sodium picosulfate admin- Table 4. Adverse events (AEs) experienced during treatment with multiple 10-mg doses of bisacodyl or sodium picosulfate istration; RAc for sodium picosulfate based on Cmax and AUC were 1.18 and 1.59, respectively. Geometric mean trough Number of subjects experiencing listed AE ® ® concentrations of total BHPM on days 4 8 ranged from 5.5 Bisacodyl group Picosulfate group 9.1 ng/mL with large inter-subject variations ¤gCV: 47.5% to 141%¥. As with bisacodyl, the steady state for sodium Abdominal discomfort 0 1 picosulfate appears to be reached on the fifth day at the Abdominal distension 2 0 latest. Geometric mean terminal half lives following single Abdominal pain 7 8 ¤ ¥ ¤ ¥ dose t1/2 and at steady-state t1/2,ss administration of Diarrhea 7 7 sodium picosulfate were similar to those observed with Dizziness 1 1 bisacodyl, being 7.3 and 10.0 h, respectively. Also similar to Fatigue 0 1 ¤ ¥ bisacodyl, the apparent plasma clearance CL/F, CL/Fss Flatulence 0 1 was low, i.e., 459 and 349 mL/min after a single dose and at Headache 4 2 steady state, respectively, and the volume of distribution was Migraine 1 0 high at 291 L after a single dose and 300 L at steady state. Myalgia 1 0 Urinary excretion of BHPM after oral administration of 10 mg bisacodyl or 10 mg sodium Nasopharyngitis 2 0 picosulfate: Urinary excretion of total BHPM accounted Nausea 0 2 for 13.8% and 17.0% of the bisacodyl dose over the intervals Scleral hemorrhage 1 0 0®24 h and 0®48 h, respectively. For picosulfate, the fractional urinary excretion of total BHPM over the intervals 0®24 h and 0®48 h was 9.1% and 10.4%, respectively. At commonly used for treating constipation leads to excretion of steady state, urinary excretion of total BHPM over the dosing their common active moiety, BHPM, in breast milk of interval accounted for 12.0% and 13.3% of the bisacodyl and healthy lactating women. In 1972, an early pharmacokinetic picosulfate dose, respectively. BHPM renal clearance over study investigated the excretion of sodium picosulfate into the uniform dosing interval following either the first dose breast milk.21¥ Neither the parent compound nor its me- ¤ ¥ ¤ ¥ fi fi CLR,0®24 or at steady state CLR,SS was similar after both tabolites were identi ed in the milk of ve postpartum bisacodyl ¤47.8 vs. 50.0 mL/min¥ and sodium picosulfate women. However, from todayös perspective, the bioanalyt- ¤52.6 vs. 46.2 mL/min¥ administration. ical method is a major shortcoming of this study. At that time, Safety: Fifteen of the 16 subjects experienced at least milk samples were analyzed with thin-layer chromatography one adverse event ¤AE¥ during the course of the study. There and the lower limit of quantification was 0.5 µg/mL. were no serious AEs and no AE resulted in premature Therefore, the current study was conducted to confirm the discontinuation. All but one event ¤nasopharyngitis ongoing absence of excretion of the active metabolites of sodium at the end of the trial¥ resolved during the course of the picosulfate into breast milk using a bioanalytical method with study. Fifteen subjects, seven receiving bisacodyl and eight a considerably lower limit of quantification ¤1 ng/mL¥. For receiving sodium picosulfate, reported AEs during the bisacodyl, no historical data were available; however, because treatment phase. These are summarized in Table 4. The bisacodyl itself is not systemically available but shares the most common AEs were diarrhea and abdominal pain, both same active metabolite with sodium picosulfate, it was reported by seven of eight subjects treated with either assumed that also after administration of bisacodyl, no milk laxative. These events are known adverse events based on excretion of BHPM or BHPM glucuronides will take place. the pharmacological action of the compounds and can be In the current study, neither prodrug led to quantifiable expected when healthy volunteers are treated with laxatives. recovery of either free or total BHPM from breast milk Four and two subjects treated with bisacodyl and sodium following single or multiple oral administrations. In all picosulfate, respectively, reported headaches, and two subjects and at all time points, BHPM in breast milk subjects reported nasopharyngitis while on bisacodyl. All remained below the limit of detection ¤1 ng/mL¥. Hence, it but two and one of the AEs reported with use of bisacodyl appears that following oral administration of bisacodyl or and sodium picosulfate respectively were of mild intensity sodium picosulfate, BHPM, the common pre-systemically and only three required intervention. No subjects discon- formed active metabolite, is not excreted into breast milk. tinued the trial due to an AE, and no clinically relevant This indicates that there is no risk associated with the use of changes in laboratory values were observed. these two laxative drugs by lactating postpartum women with regard to transfer of the active moiety to infants Discussion through breast feeding. The primary objective of this study was to investigate The absence of excretion into breast milk of BHPM may whether oral administration of bisacodyl ¤Dulcolax¥ or not be observed with other laxatives, specifically senna. A sodium picosulfate ¤Laxoberal¥ at standard 10-mg doses study among 20 postpartum lactating women previously

Copyright © 2011 by the Japanese Society for the Study of Xenobiotics (JSSX) Bisacodyl and Sodium Picosulfate Pharmacokinetics 463 reported excretion of rhein, an active metabolite of methane ¤BHPM¥« nor its glucuronides were excreted into sennosides in human breast milk.17¥ While rhein was the milk of healthy lactating women following single or detected in breast milk, its levels varied, and no effects repeated dosing of 10 mg bisacodyl or 10 mg sodium were observed on the stool output of infants. Nonetheless, picosulfate. The disposition pharmacokinetic profiles of the the appearance of rhein in breast milk indicates a difference two agents were similar. Small differences in absorption in the excretion profile of senna-based laxatives. pharmacokinetics most likely reflect the differences in The time lag before the initial rise in plasma concen- formulations and the formation mechanism of the active trations of BHPM following oral dosing of both bisacodyl principle. Adverse events observed during the study were and sodium picosulfate reflects the dosage form of bisacodyl mostly the gastrointestinal symptoms expected with use of and the mechanism for metabolic conversion of picosulfate, laxatives, and otherwise, both drugs were well tolerated. respectively. Bisacodyl is administered as enteric coated Thus, the data indicate that sodium picosulfate and bisacodyl tablets, which do not disintegrate until they enter the colon. can be safely used during breast feeding. In contrast, sodium picosulfate, though dosed as a liquid formulation, is not metabolized nor absorbed in the stomach Acknowledgments: This study was sponsored by or small intestine, but is converted to BHPM by the enzymes Boehringer Ingelheim, Germany. The sponsor was respon- of colonic bacteria.18¥ Hence, for both bisacodyl and sible for the design of the study and the collection and picosulfate, interindividual variability observed in their lag management of the data. Xendo Drug Development BV was to onset of absorption reflects inherent physiologic variability responsible for study conduct. The authors were responsible in gastric emptying and small intestinal transit time. Mean for the analysis and interpretation of the data and the differences in lag times between the compounds may preparation of the manuscript. The authors would like to reflect the kinetics of BHPM formation in the colon, which thank Silke Luedtke, Karin Hoermann, and Sabine Loy from apparently for bisacodyl tablets ¤tablet disintegration and de- Boehringer Ingelheim GmbH & Co. KG and Johan Wemer, acetylation¥ is faster than for sodium picosulfate liquid Ruben de Jong, and Ingrid Duijkers from Xendo Drug ¤enzymatic conversion¥. Development BV. In addition, bisacodyl remains intact as its tablet formulation until it enters the colon and then dissolves, References while sodium picosulfate, as a liquid formulation, disperses 1¥ Longstreth, G. F., Thompson, W. G., Chey, W. D., Houghton, as it transits the small intestine, which in turn could fl L. A., Mearin, F. and Spiller, R. C.: Functional bowel disorders. indirectly in uence the absorption rate of BHPM in the Gastroenterology, 130¤5¥: 1480®1491 ¤2006¥. colon. These differences may explain, at least in part, the 2¥ Johanson, J. F., Sonnenberg, A. and Koch, T. R.: Clinical threefold higher C and C values for bisacodyl. Also, epidemiology of chronic constipation. J. Clin. Gastroenterol., 11: max max,ss ® ¤ ¥ the converted portion might be higher for bisacodyl, which 525 536 1989 . 3¥ Locke, G. R., III, Pemberton, J. H. and Phillips, S. F.: AGA could also explain differences in Cmax and AUC values. technical review on constipation. Gastroenterology, 119: 1766®1778 No plasma accumulation of BHPM was observed fol- ¤2000¥. lowing multiple once-daily dosing of 10 mg bisacodyl. In 4¥ Higgins, P. D. R. and Johanson, J. F.: Epidemiology of constipation contrast, a low level of accumulation of total BHPM seemed in North America: a systematic review. Am. J. Gastroenterol., 99: ® ¤ ¥ to occur with multiple once-daily doses of 10 mg sodium 750 759 2004 . 5¥ Brandt, L. J., Prather, C. M., Quigley, E. M. M., Schiller, L. R., picosulfate; however, these differences could be chance fi Schoenfeld, P. and Talley, N. J.: Systematic review on the ndings due to the low sample size. It is well established that Am. J. ¥ management of chronic constipation in North America. absorbed BHPM can be eliminated in bile and urine.16 Gastroenterol., 100:S5®S21 ¤2005¥. While this study did not evaluate biliary excretion, about 6¥ Drossman, D. A., Sandler, R. S. and McKee, D. C.: Bowel 17.0% and 12.0% of the total bisacodyl dose had been patterns among subjects not seeking health care. Use of a questionnaire to identify a population with bowel dysfunction. recovered as total BHPM in urine 48 h after a single dose and Gastroenterology, 83: 529®534 ¤1982¥. 24 h after each dose at the steady state, respectively. 7¥ Drossman, D. A., Li, Z., Andruzzi, E., Temple, R. D., Talley, Corresponding levels of urinary elimination after dosing N. J., Thompson, W. G., Whitehead, W. E., Janssens, J., sodium picosulfate were 10.4% and 13.3%, respectively; Funch-Jensen, P., Corazziari, E., Richter, J. E. and Koch, G. G.: both are similar to values reported previously. U.S. household survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig. Dis. Sci., 38: The common adverse events observed in this study were 1569®1580 ¤1993¥. those expected with use of laxatives. It needs to be 8¥ Wald, A., Scarpignato, C. and Mueller-Lissner, S. et al.:A considered that these subjects were healthy and were not multinational survey of prevalence and patterns of laxative use suffering from constipation. Adverse events were mostly of among adults with self-defined constipation. Aliment Pharmacol Ther., ® ¤ ¥ mild intensity, and none resulted in the discontinuation of 28: 917 930 2008 . 9¥ Stewart, W. F., Liberman, J. N., Sandler, R. S., Woods, M. S., treatment. Overall, both drugs were well tolerated. Stemhagen, A., Chee, E., Lipton, R. B. and Farup, C. E.: In conclusion, neither the active moiety of sodium Epidemiology of constipation ¤EPOC¥ study in the United States: picosulfate and bisacodyl ªbis-¤p-hydroxyphenyl¥-pyridyl-2- relation of clinical subtypes to sociodemographic features. Am. J.

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